Harmonic Scalpel Versus Clips for Ligation of Cystic Duct in Laparoscopic Cholecystectomy: A Systematic Review

The gold standard treatment for benign gallbladder disease is laparoscopic cholecystectomy (LC). LC is commonly performed using monopolar diathermy with ligation of the cystic duct and artery with clips. The aim of the current systematic review was to compare harmonic scalpel (HS) with clips in LC. Eligible studies were identified from PubMed, Cochrane library, Embase and Medline and meta-analysis was conducted using Review Manager 5.4. The primary outcome evaluated was bile leak while secondary outcomes evaluated were overall postoperative complications, operative time, conversion to open surgery and gall bladder perforation. Eight randomized control trials met the eligibility criteria which included a total of 1,205 patients. There was no statistically significant difference between the two groups in terms of bile leak (p = 0.56, I2=0%). With respect to the operative time (p = 0.004, I2=97%), conversion to open surgery (p = 0.02, I2=0%) and gall bladder perforation (p = 0.0001, I2=26%) HS was superior to clips. HS is an acceptable alternative to the use of clips when ligating the cystic duct.


Introduction And Background
Laparoscopic cholecystectomy (LC) is considered to be the gold standard treatment for benign gall bladder pathologies [1]. Standard LC involves the use of metal clips to ligate the cystic duct and the cystic artery prior to division with laparoscopic scissors. In some cases, monopolar electrocautery is also used to divide the cystic artery. Monopolar electrocautery still remains the preferred energy device of choice by surgeons while performing LC [2,3]. Alternative methods of bile duct ligation include linear staplers, sutures and endoloops, but these have very seldom been used [4].
The main limitation of the use of monopolar diathermy is that there is a high risk of surrounding thermal damage. Slippage of clips off the cystic duct in relation to gall bladder causes bile to spill into the surgical field and this invariably causes frequent instrument change which increases the risk of visceral-related injuries [5,6].
Harmonic scalpel (HS) is an energy device that makes use of ultrasound within the harmonic frequency range to coagulate and cut tissue. It is designed to be superior to monopolar diathermy and has the capability to seal vessels 5 to 7mm in diameter. Studies have also shown that thermal energy spread is less with HS as compared to monopolar diathermy [7].
The purpose of the current systematic review is to evaluate the role of HS in successfully sealing the cystic duct in LC as compared to standard clip ligation. The primary outcome evaluated was bile leak while secondary outcomes evaluated were overall postoperative complications, operative time, conversion to open surgery and inadvertent gall bladder perforation during surgery.

Review
Systematic review and meta-analysis were designed and reported according to Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) [8].

Search strategy
Comprehensive literature search was conducted independently by two authors from PubMed, Cochrane library, Embase and Medline. The last date of search was 21st, September, 2022. There were no publication date restrictions and only human studies were included. Keywords used for electronic searches were 'harmonic scalpel', 'ultrasonic device', 'clips', 'titanium clips', 'cholecystectomy', 'laparoscopy', 'laparoscopic cholecystectomy', 'cystic duct', 'bile leak' and 'clipless cholecystectomy'. A flow chart of included and excluded studies are shown in figure 1.

Study selection
Studies eligible for inclusion were: (1) randomized controlled trials (RCTs) comparing HS with clips in LC, (2) provided information on outcome measures and (3) information on closure of cystic duct. Studies excluded were (1) non-RCTs, (2) studies not based on closure of cystic duct, (3) open cholecystectomies, (4) case reports, observational studies, reviews and meta-analysis.

Data collection
Following data was extraxted by two authors from each study: first author, year of publication, country of origin, number of included patients, mean age, gender distribution, operative time, intraoperative gall bladder perforation, type of cystic duct closure used, duration of surgery, post operative complications, gall bladder perforation and conversion to open surgery.

Assessment of Risk of bias
Risk of bias was assessed based on Cochrane risk of bias tool [9] by two authors. Following categories were classified as low, high or unclear: random sequence generation, allocation concealment, blinding of outcome assessment, blinding of participants and personnel, selective reporting and other sources of bias. Risk of bias was decided by discussion between all authors ( Figure 2).

Statistical analysis
Review manager 5.4 was used for statistical analysis. Mean difference was calculated for continuous data at 95% confidence intervals while risk ratio at 95% confidence interval was calculated for dichotomous variables. Cochrane Q test and I2 test were used to assess heterogeneity in the included studies. 0% was considered as no heterogeneity while >50% was considered as significant heterogeneity. Random effect models and fixed effect models were used for analysis appropriately based on the calculated heterogeneity.

Results
Eight RCTs were included in our analysis comprising a total of 1205 patients. There were 547 patients that underwent LC with monopolar diathermy and clip ligation of cystic duct while 658 patients underwent LC with HS. Characteristics of the clips group and harmonic group are shown in Table 1  There was no significant difference in terms of age and no significant heterogeneity. Two of the included studies [12,17] did not record age as a mean and standard deviation and hence were not included in analysing forest plot. (Figure 3).

Bile leak
Primary outcome of our study was to evaluate bile leak between harmonic group and clips group in the early postoperative period (one week following surgery). There were 3 reported cases of bile leak in harmonic group and 5 cases in the clips group. This failed to show a statistically significant difference (p = 0.56, I 2 =0%) ( Figure 4).

Operative Time
Operative time was recorded by six studies. Operative time with harmonic group was shorter as compared to the clips group and this was statistically significant. There was a high level of heterogeneity in regards to operative time (p = 0.004, I 2 =97%)( Figure 5).

Conversion to open surgery and gall bladder perforation
In three of the included studies [10,12,17], there was no conversion of open surgery in either of the groups. There were 13 cases in the harmonic group and 81 cases in the clips group that was converted to open surgery. This was statistically significant with low heterogeneity (p = 0.02, I 2 =0%)( Figure 6).

FIGURE 6: Comparison of conversion to open surgery between harmonic group and clips group
Liao et al [16] did not have any gall bladder perforation during surgery and Catena et al [15] had not recorded gall bladder perforation in their study. There were 39 cases of gall bladder perforation in harmonic group and 89 in the clips group which was statistically significant. There was low level of heterogeneity (p = 0.0001, I 2 =26%) (Figure 7).

Post operative complications
Five studies reported post operative complications. Since the primary outcome was to evaluate bile leak this has not been included in analysis as part of post operative complications. There was no significant difference between the two groups (p=0.13, I 2 =0%)( Figure 8).

Discussion
HS works on the principle of generating high frequency ultrasound which when applied to tissue produces three main effects of cavitation, coagulation and lastly cutting [18]. Due to these effects, it limits the number of instruments required to perform a safe cholecystectomy. A standard cholecystectomy includes the use of monopolar cautery for dissection, clips for ligation of cystic artery and duct and laparoscopic scissors for division [19]. Since HS can overcome use of multiple instrumentation it invariably reduces the chance of intra operative tissue injury [20]. Heat generated from HS ranges between 60 to 90 degrees Celsius which is lower as compared to monopolar diathermy which is 150 degrees Celsius [21]. Hence the degree of thermal damage by HS is less as compared to monopolar diathermy.
The main outcome of our systematic review was to evaluate bile leak following application of clips versus use of HS. Although there were a greater number of bile leaks with clip application it was not significant. Most common cause of bile leak is from cystic duct stump and secondly from inadvertent injury to biliary tree [22]. Another reason for bile leak is the accessory duct of Lushka which can leak bile during gall bladder separation from liver bed [23]. In these situations, HS proves to be quite beneficial.
The main advantage of harmonic seen in this review was that operative time was significantly shorter as compared to use of clips. When clips are being used in cholecystectomy if often involves the use of multiple instruments to be taken in and out which adds to the operative time. HS on the other hand acts as a sole instrument to cut and seals tissue at the same time achieving hemostasis [24].
In our review, there were a greater number of cases in the clips group that converted to open surgery as compared to the harmonic group and this was found to be statistically significant and consistent with already published literature [16]. In reference to gall bladder perforation, there were more cases in the clips group where monopolar diathermy was used and this was consistent with published literature [12][13][14]. This is most likely to be due to the precision by which HS can be used laparoscopicly as compared to monopolar diathermy. Another factor can also be the greater thermal damage caused by monopolar diathermy as compared to HS. Factors such as gall bladder inflammation, operative technique, surgeons experience and patient factors such as cirrhosis and obesity will also affect the outcome of open conversion and gall bladder perforation [25].
Limitations to the current review are a smaller size of the included cohort and this can result in a potential publication bias. However, we have chosen to include only RCTs to minimise bias. Data in respect to postoperative complications and gall bladder perforation were not recoded in all studies and this will affect the overall analysis. Studies have not taken patient related factors into consideration such as but not limited to gall bladder inflammation, obesity, liver cirrhosis which can potentially affect outcomes measures.

Conclusions
The current systematic review demonstrated that HS has certain advantages over the use of clips and monopolar diathermy used in conventional LC. In respect to operative time, conversion to open surgery and gall bladder perforation HS proved to be more useful. There was no difference in terms of post operative bile leak or general post operative complications. Hence we conclude that HS is an acceptable alternative to use of clips when ligating the cystic duct.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.